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Following a previous article that focused on integrating epidemiological data from prospective cohort studies into toxicological risk assessment, this paper shifts the focus to case-control studies. Specifically, it utilizes the odds ratio (OR) as the main epidemiological measure, aligning it with the benchmark dose (BMD) methodology as the standard dose-response modeling approach to determine chemical toxicity values for regulatory risk assessment. A standardized BMD analysis framework has been established for toxicological data, including input data requirements, dose-response models, definitions of benchmark response, and consideration of model uncertainty. This framework has been enhanced by recent methods capable of handling both cohort and case-control studies using summary data that have been adjusted for confounders. The present study aims to investigate and compare the "effective count" based BMD modeling approach, merged with an algorithm used for converting odds ratio to relative risk in cohort studies with partial data information (i.e., the Wang algorithm), with the adjusted OR-based BMD analysis approach. The goal is to develop an adequate BMD modeling framework that can be generalized for analyzing published case-control study data. As in the previous study, these methods were applied to a database examining the association between bladder and lung cancer and inorganic arsenic exposure. The results indicate that estimated BMDs and BMDLs are relatively consistent across both methods. However, modeling adjusted OR values as continuous data for BMD estimation aligns better with established practices in toxicological BMD analysis, making it a more generalizable approach., (© 2024 The Author(s). Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Benchmark dose (BMD) methodology has been employed as a default dose-response modeling approach to determine the toxicity value of chemicals to support regulatory chemical risk assessment. Especially, a relatively standardized BMD analysis framework has been established for modeling toxicological data regarding the formats of input data, dose-response models, definitions of benchmark response, and model uncertainty consideration. However, the BMD approach has not been well developed for epidemiological data mainly because of the diverse designs of epidemiological studies and various formats of data reported in the literature. Although most of the epidemiological BMD analyses were developed to solve a particular question, the methods proposed in two recent studies are able to handle cohort and case-control studies using summary data with consideration of adjustments for confounders. Therefore, the purpose of the present study is to investigate and compare the "effective count"-based BMD modeling approach and adjusted relative risk (RR)-based BMD analysis approach to identify an appropriate BMD modeling framework that can be generalized for analyzing published data of prospective cohort studies for BMD analysis. The two methods were applied to the same set of studies that investigated the association between bladder and lung cancer and inorganic arsenic exposure for BMD estimation. The results suggest that estimated BMDs and BMDLs are relatively consistent; however, with the consideration of established common practice in BMD analysis, modeling adjusted RR values as continuous data for BMD estimation is a more generalizable approach harmonized with the BMD approach using toxicological data., (© 2023 The Authors. Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Public heath emergencies such as the outbreak of novel infectious diseases represent a major challenge for drug regulatory bodies, practitioners, and scientific communities. In such critical situations drug regulators and public health practitioners base their decisions on evidence generated and synthesised by scientists. The urgency and novelty of the situation create high levels of uncertainty concerning the safety and effectiveness of drugs. One key tool to mitigate such emergencies is pandemic preparedness. There seems to be, however, a lack of scholarly work on methodology for assessments of new or existing drugs during a pandemic. Issues related to risk attitudes, evidence production and evidence synthesis for drug approval require closer attention. This manuscript, therefore, engages in a conceptual analysis of relevant issues of drug assessment during a pandemic. To this end, we rely in our analysis on recent discussions in the philosophy of science and the philosophy of medicine. Important unanswered foundational questions are identified and possible ways to answer them are considered. Similar problems often have similar solutions, hence studying similar situations can provide important clues. We consider drug assessments of orphan drugs and drug assessments during endemics as similar to drug assessment during a pandemic. Furthermore, other scientific fields which cannot carry out controlled experiments may guide the methodology to draw defeasible causal inferences from imperfect data. Future contributions on methodologies for addressing the issues raised here will indeed have great potential to improve pandemic preparedness.

Contemporary debates about scientific institutions and practice feature many proposed reforms. Most of these require increased efforts from scientists. But how do scientists' incentives for effort interact? How can scientific institutions encourage scientists to invest effort in research? We explore these questions using a game-theoretic model of publication markets. We employ a base game between authors and reviewers, before assessing some of its tendencies by means of analysis and simulations. We compare how the effort expenditures of these groups interact in our model under a variety of settings, such as double-blind and open review systems. We make a number of findings, including that open review can increase the effort of authors in a range of circumstances and that these effects can manifest in a policy-relevant period of time. However, we find that open review's impact on authors' efforts is sensitive to the strength of several other influences., Competing Interests: Conflict of interestAuthors declare no conflict of interest., (© The Author(s) 2022.)

Rationale, Aims and Objectives: Recent controversies about dietary advice concerning meat demonstrate that aggregating the available evidence to assess a putative causal link between food and cancer is a challenging enterprise., Methods: We show how a tool developed for assessing putative causal links between drugs and adverse drug reactions, E-Synthesis, can be applied for food carcinogenicity assessments. The application is demonstrated on the putative causal relationship between processed meat consumption and cancer., Results: The output of the assessment is a Bayesian probability that processed meat consumption causes cancer. This Bayesian probability is calculated from a Bayesian network model, which incorporates a representation of Bradford Hill's Guidelines as probabilistic indicators of causality. We show how to determine probabilities of indicators of causality for food carcinogenicity assessments based on assessments of the International Agency for Research on Cancer., Conclusions: We find that E-Synthesis is a tool well-suited for food carcinogenicity assessments, as it enables a graphical representation of lines and weights of evidence, offers the possibility to make a great number of judgements explicit and transparent, outputs a probability of causality suitable for decision making and is flexible to aggregate different kinds of evidence., (© 2022 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

Researchers, regulatory agencies, and the pharmaceutical industry are moving towards precision pharmacovigilance as a comprehensive framework for drug safety assessment, at the service of the individual patient, by clustering specific risk groups in different databases. This article explores its implementation by focusing on: (i) designing a new data collection infrastructure, (ii) exploring new computational methods suitable for drug safety data, and (iii) providing a computer-aided framework for distributed clinical decisions with the aim of compiling a personalized information leaflet with specific reference to a drug's risks and adverse drug reactions. These goals can be achieved by using 'smart hospitals' as the principal data sources and by employing methods of precision medicine and medical statistics to supplement current public health decisions., Competing Interests: Declaration of interests The authors have no interests to declare., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Real World Evidence (RWE) and its uses are playing a growing role in medical research and inference. Prominently, the 21st Century Cures Act-approved in 2016 by the US Congress-permits the introduction of RWE for the purpose of risk-benefit assessments of medical interventions. However, appraising the quality of RWE and determining its inferential strength are, more often than not, thorny problems, because evidence production methodologies may suffer from multiple imperfections. The problem arises to aggregate multiple appraised imperfections and perform inference with RWE. In this article, we thus develop an evidence appraisal aggregation algorithm called EA3. Our algorithm employs the softmax function-a generalisation of the logistic function to multiple dimensions-which is popular in several fields: statistics, mathematical physics and artificial intelligence. We prove that EA3 has a number of desirable properties for appraising RWE and we show how the aggregated evidence appraisals computed by EA3 can support causal inferences based on RWE within a Bayesian decision making framework. We also discuss features and limitations of our approach and how to overcome some shortcomings. We conclude with a look ahead at the use of RWE., Competing Interests: The authors have declared that no competing interests exist.

Rationale, Aims and Objectives: The diversity of types of evidence (eg, case reports, animal studies and observational studies) makes the assessment of a drug's safety profile into a formidable challenge. While frequentist uncertain inference struggles in aggregating these signals, the more flexible Bayesian approaches seem better suited for this quest. Artificial Intelligence (AI) offers great promise to these approaches for information retrieval, decision support, and learning probabilities from data., Methods: E-Synthesis is a Bayesian framework for drug safety assessments built on philosophical principles and considerations. It aims to aggregate all the available information, in order to provide a Bayesian probability of a drug causing an adverse reaction. AI systems are being developed for evidence aggregation in medicine, which increasingly are automated., Results: We find that AI can help E-Synthesis with information retrieval, usability (graphical decision-making aids), learning Bayes factors from historical data, assessing quality of information and determining conditional probabilities for the so-called 'indicators' of causation for E-Synthesis. Vice versa, E-Synthesis offers a solid methodological basis for (semi-)automated evidence aggregation with AI systems., Conclusions: Properly applied, AI can help the transition of philosophical principles and considerations concerning evidence aggregation for drug safety to a tool that can be used in practice., (© 2021 The Authors. Journal of Evaluation in Clinical Practice published by John Wiley & Sons Ltd.)

Background: Evidence suggesting adverse drug reactions often emerges unsystematically and unpredictably in form of anecdotal reports, case series and survey data. Safety trials and observational studies also provide crucial information regarding the (un-)safety of drugs. Hence, integrating multiple types of pharmacovigilance evidence is key to minimising the risks of harm. Methods: In previous work, we began the development of a Bayesian framework for aggregating multiple types of evidence to assess the probability of a putative causal link between drugs and side effects. This framework arose out of a philosophical analysis of the Bradford Hill Guidelines. In this article, we expand the Bayesian framework and add "evidential modulators," which bear on the assessment of the reliability of incoming study results. The overall framework for evidence synthesis, "E-Synthesis", is then applied to a case study. Results: Theoretically and computationally, E-Synthesis exploits coherence of partly or fully independent evidence converging towards the hypothesis of interest (or of conflicting evidence with respect to it), in order to update its posterior probability. With respect to other frameworks for evidence synthesis, our Bayesian model has the unique feature of grounding its inferential machinery on a consolidated theory of hypothesis confirmation (Bayesian epistemology), and in allowing any data from heterogeneous sources (cell-data, clinical trials, epidemiological studies), and methods (e.g., frequentist hypothesis testing, Bayesian adaptive trials, etc.) to be quantitatively integrated into the same inferential framework. Conclusions: E-Synthesis is highly flexible concerning the allowed input, while at the same time relying on a consistent computational system, that is philosophically and statistically grounded. Furthermore, by introducing evidential modulators, and thereby breaking up the different dimensions of evidence (strength, relevance, reliability), E-Synthesis allows them to be explicitly tracked in updating causal hypotheses., (Copyright © 2019 De Pretis, Landes and Osimani.)

Today's surge of big data coming from multiple sources is raising the stakes that pharmacovigilance has to win, making evidence synthesis a more and more robust approach in the field. In this scenario, many scholars believe that new computational methods derived from data mining will effectively enhance the detection of early warning signals for adverse drug reactions, solving the gauntlets that post-marketing surveillance requires. This article highlights the need for a philosophical approach in order to fully realize a pharmacovigilance 2.0 revolution. A state of the art on evidence synthesis is presented, followed by the illustration of E-Synthesis , a Bayesian framework for causal assessment. Computational results regarding dose-response evidence are shown at the end of this article.